Age-dependent impairment of metabotropic glutamate receptor 2-dependent long-term depression in the mouse striatum by chronic ethanol exposure

Abstract Chronic alcohol exposure is associated with increased reliance on behavioral strategies involving the dorsolateral striatum (DLS), including habitual or stimulus-response behaviors. Presynaptic G protein-coupled receptors (GPCRs) on cortical and thalamic inputs to the DLS inhibit glutamate release, and alcohol-induced disruption of presynaptic GPCR function represents a mechanism by which alcohol could disinhibit DLS neurons and thus bias towards use of DLS-dependent behaviors. Metabotropic glutamate receptor 2 (mGlu 2 ) is a G i/o -coupled GPCR that robustly modulates glutamate transmission in the DLS, inducing long-term depression (LTD) at both cortical and thalamic synapses. Loss of mGlu 2 function has recently been associated with increased ethanol seeking and consumption, but the ability of alcohol to produce adaptations in mGlu 2 function in the DLS has not been investigated. We exposed male C57Bl/6J mice to a two-week chronic intermittent ethanol (CIE) paradigm followed by a brief withdrawal period, then used whole-cell patch clamp recordings of glutamatergic transmission in the striatum to assess CIE effects on mGlu 2 -mediated synaptic plasticity. We report that CIE differentially disrupts mGlu 2 -mediated long-term depression in the DLS vs. dorsomedial striatum (DMS). Interestingly, CIE-induced impairment of mGlu 2 -LTD in the dorsolateral striatum is only observed when alcohol exposure occurs during adolescence. Incubation of striatal slices from CIE-exposed adolescent mice with a positive allosteric modulator of mGlu 2 fully rescues mGlu 2 -LTD. In contrast to the two-week CIE paradigm, acute exposure of striatal slices to ethanol concentrations that mimic ethanol levels during CIE fails to disrupt mGlu 2 -LTD. We did not observe a reduction of mGlu 2 mRNA or protein levels following CIE, suggesting that alcohol effects on mGlu 2 occur at the functional level. Our findings contribute to growing evidence that adolescents are uniquely vulnerable to certain alcohol-induced neuroadaptations, and identify enhancement of mGlu 2 activity as a strategy to reverse the effects of adolescent alcohol exposure on DLS physiology.